Hong WangThe Fisher Center for Alzheimer s Disease Research and the Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, USAJ Biol Chem 279:40560-6. 2004

Modulation of gamma-secretase specificity using small molecule allosteric inhibitors

..Therefore, this work not only provides a unique system for elucidating the reaction mechanism of rhomboid but also will facilitate the characterization of other intramembrane proteases as well as non-protease membrane proteins...

..Two routes leading from 19 to compounds 2 and 3 are evaluated. The application of 3 as an activity-based probe has been demonstrated by localizing gamma-secretase activity in the plasma membrane of intact cells...

Structure of gamma-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy

Fabiana RenziDepartment of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York 10029, USAJ Biol Chem 286:21440-9. 2011

..Comparison with the structure of a trimeric pre-activation intermediate suggested that the incorporation of PEN-2 might contribute to the maturation of the active site architecture...

Hong WangThe Fisher Center for Alzheimer s Disease Research and the Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, USAJ Biol Chem 279:40560-6. 2004

....

Modulation of gamma-secretase specificity using small molecule allosteric inhibitors

..This work reveals an unforeseen role for α-secretase in generating an endogenous γ-secretase inhibitor that down-regulates the production of Aβ. Deregulation of this feedback mechanism may contribute to the pathogenesis of AD...

Processing of Notch and amyloid precursor protein by gamma-secretase is spatially distinct

..Furthermore, the fact that inhibitors first target gamma-secretase in the plasma membrane for Notch processing, and not for APP, will have important implications for drug development to treat Alzheimer's disease and cancer...

..Various models are proposed and discussed. Despite the progress of GSM research, many outstanding issues remain to be investigated to achieve the ultimate goal of developing GSMs as effective AD therapies. ..

Total synthesis as a resource in drug discovery: the first in vivo evaluation of panaxytriol and its derivatives

..This validated assay can readily be used for primary screening against large chemical libraries searching for novel inhibitors of gamma-secretase activity that may represent potential therapeutics for AD and a variety of neoplasms...

..These data underscore the need for studying endogenous gamma-secretase to fully understand of the biology of gamma-secretase and its complexity as a molecular target for the development of disease therapeutics...

Total synthesis of (+/-)-jiadifenin and studies directed to understanding its SAR: probing mechanistic and stereochemical issues in palladium-mediated allylation of enolate-like structures

David A CarcacheLaboratory for Bioorganic Chemistry, Sloan Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USAJ Am Chem Soc 128:1016-22. 2006

..While in the particular case at hand, we find very little difference in stereochemical outcome as one partitions between the inter- and intramolecular pathways, the techniques employed are applicable to other systems...

..With a focus on material throughput and convergency, the five peptide fragments were assembled into the native ATAD2 bromodomain region with a total of three HPLC events in 8% overall yield from the fragments. ..

Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 gamma-secretase complexes